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Abstract:

The present invention relates to phenalkylamine derivatives of the
formula (I) or (II)
##STR00001##
or a physiologically tolerated salt thereof.
The invention relates to pharmaceutical compositions comprising such
phenalkylamine derivatives, and the use of such phenalkylamine
derivatives for therapeutic purposes. The phenalkylamine derivatives are
GlyT1 inhibitors.

16. Compound as claimed in claim 1, wherein R4a, R4b are
optionally substituted C1-C6-alkylene, wherein one --CH2--
of C1-C4-alkylene may be replaced by an oxygen atom.

17. Compound as claimed in claim 1, which is a compound of formula (I)
wherein R1 is C1-C6-alkyl or optionally substituted
C3-C12-heterocyclyl; W is a bond; A1 is a bond; Q is
--S(O)2--; Y is NR9; A2 is C1-C4-alkylene
X1 --O-- X4 --O-- or NR19; n is 1; R6 is hydrogen;
R2 is hydrogen; R3 is hydrogen; X2 is CR12aR12b;
X3 is a bond; R5 is phenyl; Y1 is a bond; Y2 is
>CR15aR15b; R4a is hydrogen; R4b is hydrogen;
R12a is hydrogen; R12b is hydrogen; R15a is hydrogen;
R15b is hydrogen; and R19 is C1-C6-alkyl, or which is
a compound of formula (II) wherein R1 is
C3-C12-cycloalkyl-C1-C4-alkyl, or optionally
substituted C3-C12-heterocyclyl; W is a bond; A1 is a
bond; Q is --S(O)2-- or --C(O)--; m is 1 or 2; R6 is hydrogen;
R2 is hydrogen; R3 is hydrogen; Y1 is a bond; Y2 is
>CR15aR15b; R4a is hydrogen, or C1-C6-alkyl;
R4b is hydrogen or C1-C6-alkyl; X2 is
CR12aR12b; X3 is a bond; R5 is phenyl; R12a is
hydrogen; R12b is hydrogen; R15a is hydrogen; and R15b is
hydrogen.

19. Pharmaceutical composition which comprises a carrier and a compound
of claim 1.

20. A method for treating a neurologic or psychiatric disorder or pain in
a mammalian patient in need thereof which comprises administering to the
patient a therapeutically effective amount of a compound of claim 1.

Description:

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This claims priority to U.S. Provisional Patent Application No.
61/373,571, filed on Aug. 13, 2010, the contents of which are hereby
incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to phenalkylamine derivatives,
pharmaceutical compositions comprising such phenalkylamine derivatives,
and the use of such phenalkylamine derivatives for therapeutic purposes.
The phenalkylamine derivatives are GlyT1 inhibitors.

[0003] Dysfunction of glutamatergic pathways has been implicated in a
number of disease states in the human central nervous system (CNS)
including but not limited to schizophrenia, cognitive deficits, dementia,
Parkinson disease, Alzheimer disease and bipolar disorder. A large number
of studies in animal models lend support to the NMDA hypofunction
hypothesis of schizophrenia.

[0004] NMDA receptor function can be modulated by altering the
availability of the co-agonist glycine. This approach has the critical
advantage of maintaining activity-dependent activation of the NMDA
receptor because an increase in the synaptic concentration of glycine
will not produce an activation of NMDA receptors in the absence of
glutamate. Since synaptic glutamate levels are tightly maintained by high
affinity transport mechanisms, an increased activation of the glycine
site will only enhance the NMDA component of activated synapses.

[0005] Two specific glycine transporters, GlyT1 and GlyT2 have been
identified and shown to belong to the Na/Cl-dependent family of
neurotransmitter transporters which includes taurine, gamma-aminobutyric
acid (GABA), proline, monoamines and orphan transporters. GlyT1 and GlyT2
have been isolated from different species and shown to have only 50%
identity at the amino acid level. They also have a different pattern of
expression in mammalian central nervous system, with GlyT2 being
expressed in spinal cord, brainstem and cerebellum and GlyT1 present in
these regions as well as forebrain areas such as cortex, hippocampus,
septum and thalamus. At the cellular level, GlyT2 has been reported to be
expressed by glycinergic nerve endings in rat spinal cord whereas GlyT1
appears to be preferentially expressed by glial cells. These expression
studies have led to the suggestion that GlyT2 is predominantly
responsible for glycine uptake at glycinergic synapses whereas GlyT1 is
involved in monitoring glycine concentration in the vicinity of NMDA
receptor expressing synapses. Recent functional studies in rat have shown
that blockade of GlyT1 with the potent inhibitor
(N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])-sarcosine (NFPS)
potentiates NMDA receptor activity and NMDA receptor-dependent long-term
potentiation in rat.

[0006] Molecular cloning has further revealed the existence of three
variants of GlyT1, termed GlyT-1a, GlyT-1b and GlyT-1c, each of which
displays a unique distribution in the brain and peripheral tissues. The
variants arise by differential splicing and exon usage, and differ in
their N-terminal regions.

[0007] The physiological effects of GlyT1 in forebrain regions together
with clinical reports showing the beneficial effects of GlyT1 inhibitor
sarcosine in improving symptoms in schizophrenia patients suggest that
selective GlyT1 inhibitors represent a new class of antipsychotic drugs.

[0008] Glycine transporter inhibitors are already known in the art, for
example:

[0069] Thus, the term phenalkylamine derivative is used herein to denote
in particular phenethylamines (Y1 is a bond) and phenpropylamines
(Y1 is >CR14aR14b).

[0070] Said compounds of formula (I) or (II), i.e., the phenalkylamine
derivatives of formula (I) or (II) and their physiologically tolerated
salts, are glycine transporter inhibitors and thus useful as
pharmaceuticals.

[0071] The present invention thus further relates to the compounds of
formula (I) or (II) for use in therapy.

[0072] The present invention also relates to pharmaceutical compositions
which comprise a carrier and a compound of formula (I) or (II).

[0073] In particular, said compounds, i.e., the phenalkylamine derivatives
and their physiologically tolerated salts, are inhibitors of the glycine
transporter GlyT1.

[0074] The present invention thus further relates to the compounds of
formula (I) or (II) for use in inhibiting the glycine transporter.

[0075] The present invention also relates to the use of the compounds of
formula (I) or (II) in the manufacture of a medicament for inhibiting the
glycine transporter GlyT1 and corresponding methods of inhibiting the
glycine transporter GlyT1.

[0076] Glycine transport inhibitors and in particular inhibitors of the
glycine transporter GlyT1 are known to be useful in treating a variety of
neurologic and psychiatric disorders.

[0077] The present invention thus further relates to the compounds of
formula (I) or (II) for use in treating a neurologic or psychiatric
disorder.

[0078] The present invention further relates to the compounds of formula
(I) or (II) for use in treating pain.

[0079] The present invention also relates to the use of the compounds of
formula (I) or (II) in the manufacture of a medicament for treating a
neurologic or psychiatric disorder and corresponding methods of treating
said disorders. The present invention also relates to the use of the
compounds of formula (I) or (II) in the manufacture of a medicament for
treating pain and corresponding methods of treating pain.

DETAILED DESCRIPTION OF THE INVENTION

[0080] Provided that the phenalkylamine derivatives of the formula (I) or
(II) of a given constitution may exist in different spatial arrangements,
for example if they possess one or more centers of asymmetry,
polysubstituted rings or double bonds, or as different tautomers, it is
also possible to use enantiomeric mixtures, in particular racemates,
diastereomeric mixtures and tautomeric mixtures, preferably, however, the
respective essentially pure enantiomers, diastereomers and tautomers of
the compounds of formula (I) or (II) and/or of their salts.

[0081] According to one embodiment, an enantiomer of the phenalkylamine
derivatives of the present invention has the following formula:

[0084] The present invention moreover relates to compounds of formula (I)
as defined herein, wherein at least one of the atoms has been replaced by
its stable, non-radioactive isotope (e.g., hydrogen by deuterium,
12C by 13C, 14N by 15N, 16O by 18O) and
preferably wherein at least one hydrogen atom has been replaced by a
deuterium atom.

[0085] Of course, such compounds contain more of the respective isotope
than this naturally occurs and thus is anyway present in the compounds
(I).

[0086] Stable isotopes (e.g., deuterium, 13C, 15N, 18O) are
nonradioactive isotopes which contain one or more additional neutron than
the normally abundant isotope of the respective atom. Deuterated
compounds have been used in pharmaceutical research to investigate the in
vivo metabolic fate of the compounds by evaluation of the mechanism of
action and metabolic pathway of the non-deuterated parent compound (Blake
et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are
important in the design of safe, effective therapeutic drugs, either
because the in vivo active compound administered to the patient or
because the metabolites produced from the parent compound prove to be
toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14,
pp. 2-36, Academic Press, London, 1985; Kato et al., J. Labelled Comp.
Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J. Physiol.
Pharmacol., 77, 79-88 (1999).

[0087] Incorporation of a heavy atom particularly substitution of
deuterium for hydrogen, can give rise to an isotope effect that could
alter the pharmacokinetics of the drug. This effect is usually
insignificant if the label is placed at a metabolically inert position of
the molecule.

[0088] Stable isotope labeling of a drug can alter its physico-chemical
properties such as pKa and lipid solubility. These changes may influence
the fate of the drug at different steps along its passage through the
body. Absorption, distribution, metabolism or excretion can be changed.
Absorption and distribution are processes that depend primarily on the
molecular size and the lipophilicity of the substance. These effects and
alterations can affect the pharmacodynamic response of the drug molecule
if the isotopic substitution affects a region involved in a
ligand-receptor interaction.

[0089] Drug metabolism can give rise to large isotopic effect if the
breaking of a chemical bond to a deuterium atom is the rate limiting step
in the process. While some of the physical properties of a stable
isotope-labeled molecule are different from those of the unlabeled one,
the chemical and biological properties are the same, with one important
exception: because of the increased mass of the heavy isotope, any bond
involving the heavy isotope and another atom will be stronger than the
same bond between the light isotope and that atom. In any reaction in
which the breaking of this bond is the rate limiting step, the reaction
will proceed slower for the molecule with the heavy isotope due to
"kinetic isotope effect". A reaction involving breaking a C--D bond can
be up to 700 percent slower than a similar reaction involving breaking a
C--H bond. If the C--D bond is not involved in any of the steps leading
to the metabolite, there may not be any effect to alter the behavior of
the drug. If a deuterium is placed at a site involved in the metabolism
of a drug, an isotope effect will be observed only if breaking of the
C--D bond is the rate limiting step. There is evidence to suggest that
whenever cleavage of an aliphatic C--H bond occurs, usually by oxidation
catalyzed by a mixed-function oxidase, replacement of the hydrogen by
deuterium will lead to observable isotope effect. It is also important to
understand that the incorporation of deuterium at the site of metabolism
slows its rate to the point where another metabolite produced by attack
at a carbon atom not substituted by deuterium becomes the major pathway a
process called "metabolic switching".

[0091] The weight percentage of hydrogen in a mammal (approximately 9%)
and natural abundance of deuterium (approximately 0.015%) indicates that
a 70 kg human normally contains nearly a gram of deuterium. Furthermore,
replacement of up to about 15% of normal hydrogen with deuterium has been
effected and maintained for a period of days to weeks in mammals,
including rodents and dogs, with minimal observed adverse effects (Czajka
D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F, Ann.
New York Acad. Sci 1960 84: 736; Czakja D M et al., Am. J. Physiol. 1961
201: 357). Higher deuterium concentrations, usually in excess of 20%, can
be toxic in animals. However, acute replacement of as high as 15%-23% of
the hydrogen in humans' fluids with deuterium was found not to cause
toxicity (Blagojevic N et al. in "Dosimetry & Treatment Planning for
Neutron Capture Therapy", Zamenhof R, Solares G and Harling O Eds. 1994.
Advanced Medical Publishing, Madison Wis. pp. 125-134; Diabetes Metab.
23: 251 (1997)).

[0093] The hydrogens present on a particular organic compound have
different capacities for exchange with deuterium. Certain hydrogen atoms
are easily exchangeable under physiological conditions and, if replaced
by deuterium atoms, it is expected that they will readily exchange for
protons after administration to a patient. Certain hydrogen atoms may be
exchanged for deuterium atoms by the action of a deuteric acid such as
D2SO4/D2O. Alternatively, deuterium atoms may be
incorporated in various combinations during the synthesis of compounds of
the invention. Certain hydrogen atoms are not easily exchangeable for
deuterium atoms. However, deuterium atoms at the remaining positions may
be incorporated by the use of deuterated starting materials or
intermediates during the construction of compounds of the invention.

[0095] The organic moieties mentioned in the above definitions of the
variables are--like the term halogen--collective terms for individual
listings of the individual group members. The prefix Cn-Cm
indicates in each case the possible number of carbon atoms in the group.

[0097] The term halogen denotes in each case fluorine, bromine, chlorine
or iodine, in particular fluorine or chlorine.

[0098] C1-C4-Alkyl is a straight-chain or branched alkyl group
having from 1 to 4 carbon atoms. Examples of an alkyl group are methyl,
C2-C4-alkyl such as ethyl, n-propyl, iso-propyl, n-butyl,
2-butyl, iso-butyl or tert-butyl. C1-C2-Alkyl is methyl or
ethyl, C1-C3-alkyl is additionally n-propyl or isopropyl.

[0101] C6-C12-Aryl-C1-C4-alkyl is a straight-chain or
branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon
atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon
atoms, wherein one hydrogen atom is replaced by C6-C12-aryl,
such as in benzyl.

[0102] Hydroxy-C1-C4-alkyl is a straight-chain or branched alkyl
group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more
preferably 1 or 2 carbon atoms, wherein one or two hydrogen atoms are
replaced by one or two hydroxyl groups, such as in hydroxymethyl,
(R)-1-hydroxyethyl, (S)-1-hydroxyethyl, 2-hydroxyethyl,
(R)-1-hydroxypropyl, (S)-1-hydroxypropyl, 2-hydroxypropyl,
3-hydroxypropyl, (R)-2-hydroxy-1-methylethyl,
(S)-2-hydroxy-1-methylethyl, 2-hydroxy-1-(hydroxymethyl)ethyl,
(R)-1-hydroxybutyl, (S)-1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl,
4-hydroxybutyl.

[0104] Amino-C1-C4-alkyl is a straight-chain or branched alkyl
group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more
preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms,
wherein one hydrogen atom is replaced by an amino group, such as in
aminomethyl, 2-aminoethyl.

[0105] C1-C6-Alkylamino-C1-C4-alkyl is a
straight-chain or branched alkyl group having 1 to 4 carbon atoms,
preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in
particular 1 or two carbon atoms, wherein one hydrogen atom is replaced
by a C1-C6-alkylamino group, in particular by a
C1-C4-alkylamino group, such as in methylaminomethyl,
ethylaminomethyl, n-propylaminomethyl, iso-propylaminomethyl,
n-butylaminomethyl, 2-butylaminomethyl, iso-butylaminomethyl or
tert-butylaminomethyl.

[0106] Di-C1-C6-Alkylamino-C1-C4-alkyl is a
straight-chain or branched alkyl group having 1 to 4 carbon atoms,
preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in
particular 1 or two carbon atoms, wherein one hydrogen atom is replaced
by a di-C1-C6-Alkylamino group, in particular by a
di-C1-C4-alkylamino group, such as in dimethylaminomethyl.

[0107] C1-C6-Alkylcarbonylamino-C1-C4-alkyl is a
straight-chain or branched alkyl group having 1 to 4 carbon atoms,
preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in
particular 1 or two carbon atoms, wherein one hydrogen atom is replaced
by a C1-C6-alkylcarbonylamino group, in particular by a
C1-C4-alkylcarbonylamino group, such as in
methylcarbonylaminomethyl, ethylcarbonylaminomethyl,
n-propylcarbonylaminomethyl, iso-propylcarbonylaminomethyl,
n-butylcarbonylaminomethyl, 2-butylcarbonylaminomethyl,
iso-butylcarbonylaminomethyl or tert-butylcarbonylaminomethyl.

[0108] C1-C6-Alkylaminocarbonylamino-C1-C4-alkyl is a
straight-chain or branched alkyl group having 1 to 4 carbon atoms,
preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in
particular 1 or two carbon atoms, wherein one hydrogen atom is replaced
by a C1-C6-alkylaminocarbonylamino group, in particular by a
C1-C4-alkylaminocarbonylamino group, such as in
methylaminocarbonylaminomethyl, ethylaminocarbonylaminomethyl,
n-propylaminocarbonylaminomethyl, iso-propylaminocarbonylaminomethyl,
n-butylaminocarbonylaminomethyl, 2-butylaminocarbonylaminomethyl,
iso-butylaminocarbonylaminomethyl or tert-butylaminocarbonylaminomethyl.

[0109] Di-C1-C6-alkylaminocarbonylamino-C1-C4-alkyl is
a straight-chain or branched alkyl group having 1 to 4 carbon atoms,
preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in
particular 1 or two carbon atoms, wherein one hydrogen atom is replaced
by a di-C1-C6-alkylaminocarbonylamino group, in particular by a
di-C1-C4-alkylaminocarbonylamino group, such as in
dimethylaminocarbonylaminomethyl, dimethylaminocarbonylaminoethyl,
dimethylaminocarbonylaminon-propyl.

[0110] C1-C6-Alkylsulfonylamino-C1-C4-alkyl is a
straight-chain or branched alkyl group having 1 to 4 carbon atoms,
preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in
particular 1 or two carbon atoms, wherein one hydrogen atom is replaced
by a C1-C6-alkylsulfonylamino group, in particular by a
C1-C4-alkylsulfonylamino group, such as in
methylsulfonylaminomethyl, ethylsulfonylaminomethyl,
n-propylsulfonylaminomethyl, iso-propylsulfonylaminomethyl,
n-butylsulfonylaminomethyl, 2-butylsulfonylaminomethyl,
iso-butylsulfonylaminomethyl or tert-butylsulfonylaminomethyl.

[0111] (C6-C12-Aryl-C1-C6-alkyl)amino-C1-C4
alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon
atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon
atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is
replaced by a (C6-C12-aryl-C1-C6-alkyl)amino group,
in particular a (C6-C12-aryl-C1-C2-alkyl)amino group,
such as in benzylaminomethyl.

[0112] C3-C12-Heterocyclyl-C1-C4-alkyl is a
straight-chain or branched alkyl group having 1 to 4 carbon atoms,
preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in
particular 1 or two carbon atoms, wherein one hydrogen atom is replaced
by C3-C12-heterocyclyl, such as in N-pyrrolidinylmethyl,
N-piperidinylmethyl, N-morpholinylmethyl.

[0113] C3-C12-Cycloalkyl is a cycloaliphatic radical having from
3 to 12 carbon atoms. In particular, 3 to 6 carbon atoms form the cyclic
structure, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The cyclic structure may be unsubstituted or may carry 1, 2, 3 or 4
C1-C4 alkyl radicals, preferably one or more methyl radicals.

[0114] Carbonyl is >C═O.

[0115] C1-C6-Alkylcarbonyl is a radical of the formula
R--C(O)--, wherein R is an alkyl radical having from 1 to 6, preferably
from 1 to 4, in particular 1 or 2 carbon atoms as defined herein.
Examples include acetyl, propionyl, n-butyryl, 2-methylpropionyl,
pivaloyl.

[0116] Halogenated C1-C6-alkylcarbonyl is
C1-C6-alkylcarbonyl as defined herein, wherein at least one,
e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4
or a corresponding number of identical or different halogen atoms.
Examples include fluoromethylcarbonyl, difluoromethylcarbonyl,
trifluoromethylcarbonyl. Further examples are
1,1,1-trifluoroeth-2-ylcarbonyl, 1,1,1-trifluoroprop-3-ylcarbonyl.

[0117] C6-C12-Arylcarbonyl is a radical of the formula
R--C(O)--, wherein R is an aryl radical having from 6 to 12 carbon atoms
as defined herein. Examples include benzoyl.

[0118] C1-C6-Alkoxycarbonyl is a radical of the formula
R--O--C(O)--, wherein R is an alkyl radical having from 1 to 6,
preferably from 1 to 4, in particular 1 or 2 carbon atoms as defined
herein. Examples include methoxycarbonyl and tert-butyloxycarbonyl.

[0119] Halogenated C1-C6-alkoxycarbonyl is a
C1-C6-alkoxycarbonyl as defined herein, wherein at least one,
e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4
or a corresponding number of identical or different halogen atoms.

[0120] C6-C12-Aryloxycarbonyl is a radical of the formula
R--O--C(O)--, wherein R is an aryl radical having from 6 to 12 carbon
atoms as defined herein. Examples include phenoxycarbonyl.

[0121] Cyano is --C≡N.

[0122] Aminocarbonyl is NH2C(O)--.

[0123] C1-C6-Alkylaminocarbonyl is a radical of the formula
R--NH--C(O)--, wherein R is an alkyl radical having from 1 to 6,
preferably from 1 to 4, in particular 1 or 2 carbon atoms as defined
herein. Examples include methylaminocarbonyl.

[0124] (Halogenated C1-C4-alkyl)aminocarbonyl is a
C1-C4-alkylaminocarbonyl as defined herein, wherein at least
one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2,
3, 4 or a corresponding number of identical or different hydrogen atoms.

[0125] C6-C12-Arylaminocarbonyl is a radical of the formula
R--NH--C(O)--, wherein R is an aryl radical having from 6 to 12 carbon
atoms as defined herein. Examples include phenylaminocarbonyl.

[0136] C1-C6-Hydroxyalkoxy is an alkoxy radical having from 1 to
6, preferably from 1 to 4 carbon atoms as defined herein, wherein one or
two hydrogen atoms are replaced by hydroxy. Examples include
2-hydroxyethoxy, 3-hydroxypropoxy, 2-hydroxypropoxy,
1-methyl-2-hydroxyethoxy and the like.

[0137] C1-C6-Alkoxy-C1-C4-alkoxy is an alkoxy radical
having from 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms as
defined herein, wherein one or two hydrogen atoms are replaced by one or
two alkoxy radicals having from 1 to 6, preferably from 1 to 4 carbon
atoms as defined herein. Examples include methoxymethoxy,
2-methoxyethoxy, 1-methoxyethoxy, 3-methoxypropoxy, 2-methoxypropoxy,
1-methyl-1-methoxyethoxy, ethoxymethoxy, 2-ethoxyethoxy, 1-ethoxyethoxy,
3-ethoxypropoxy, 2-ethoxypropoxy, 1-methyl-1-ethoxyethoxy and the like.

[0138] Amino-C1-C4-alkoxy is an alkoxy radical having from 1 to
4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen
atom is replaced by an amino group. Examples include 2-aminoethoxy.

[0139] C1-C6-Alkylamino-C1-C4-alkoxy is an alkoxy
radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined
herein, wherein one hydrogen atom is replaced by an alkylamino group
having from 1 to 6, preferably from 1 to 4 carbon atoms as defined
herein. Examples include methylaminomethoxy, ethylaminomethoxy,
n-propylaminomethoxy, iso-propylaminomethoxy, n-butylaminomethoxy,
2-butylaminomethoxy, iso-butylaminomethoxy, tert-butylaminomethoxy,
2-(methylamino)ethoxy, 2-(ethylamino)ethoxy, 2-(n-propylamino)ethoxy,
2-(iso-propylamino)ethoxy, 2-(n-butylamino)ethoxy,
2-(2-butylamino)ethoxy, 2-(iso-butylamino)ethoxy,
2-(tert-butylamino)ethoxy.

[0140] Di-C1-C6-alkylamino-C1-C4-alkoxy is an alkoxy
radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined
herein, wherein one hydrogen atom is replaced by a di-alkylamino group
having from 1 to 6, preferably from 1 to 4 carbon atoms as defined
herein. Examples include dimethylaminomethoxy, diethylaminomethoxy,
N-methyl-N-ethylamino)-ethoxy, 2-(dimethylamino)ethoxy,
2-(diethylamino)ethoxy, 2-(N-methyl-N-ethylamino)-ethoxy.

[0141] C1-C6-Alkylcarbonylamino-C1-C4-alkoxy is an
alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as
defined herein, wherein one hydrogen atom is replaced by an
alkylcarbonylamino group wherein the alkyl group has from 1 to 6,
preferably from 1 to 4 carbon atoms as defined herein. Examples include
methylcarbonylaminomethoxy, ethylcarbonylaminomethoxy,
n-propylcarbonylaminomethoxy, iso-propylcarbonylaminomethoxy,
n-butylcarbonylaminomethoxy, 2-butylcarbonylaminomethoxy,
iso-butylcarbonylaminomethoxy, tert-butylcarbonylaminomethoxy,
2-(methylcarbonylamino)ethoxy, 2-(ethylcarbonylamino)ethoxy,
2-(n-propylcarbonylamino)ethoxy, 2-(iso-propylcarbonylamino)ethoxy,
2-(n-butylcarbonylamino)ethoxy, 2-(2-butylcarbonylamino)ethoxy,
2-(iso-butylcarbonylamino)ethoxy, 2-(tert-butylcarbonylamino)ethoxy.

[0142] C6-C12-Arylcarbonylamino-C1-C4-alkoxy is an
alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as
defined herein, wherein one hydrogen atom is replaced by a
C6-C12-arylcarbonylamino group as defined herein. Examples
include 2-(benzoylamino)-ethoxy.

[0143] C1-C6-Alkoxycarbonylamino-C1-C4-alkoxy is an
alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as
defined herein, wherein one hydrogen atom is replaced by an
alkoxycarbonylamino group wherein the alkoxy group has from 1 to 6,
preferably from 1 to 4 carbon atoms as defined herein. Examples include
methoxycarbonylaminomethoxy, ethoxycarbonylaminomethoxy,
n-propoxycarbonylaminomethoxy, iso-propoxycarbonylaminomethoxy,
n-butoxycarbonylaminomethoxy, 2-butoxycarbonylaminomethoxy,
iso-butoxycarbonylaminomethoxy, tert-butoxycarbonylaminomethoxy,
2-(methoxycarbonylamino)ethoxy, 2-(ethoxycarbonylamino)ethoxy,
2-(n-propoxycarbonylamino)ethoxy, 2-(iso-propoxycarbonylamino)ethoxy,
2-(n-butoxycarbonylamino)ethoxy, 2-(2-butoxycarbonylamino)ethoxy,
2-(iso-butoxycarbonylamino)ethoxy, 2-(tert-butoxycarbonylamino)ethoxy.

[0144] C2-C6-Alkenyloxy is a radical of the formula R--O--,
wherein R is a straight-chain or branched alkenyl group having from 2 to
6, in particular 2 to 4 carbon atoms. Examples include vinyloxy, allyloxy
(2-propen-1-yloxy), 1-propen-1-yloxy, 2-propen-2-yloxy, methallyloxy
(2-methylprop-2-en-1-yloxy) and the like. C3-C5-Alkenyloxy is,
in particular, allyloxy, 1-methylprop-2-en-1-yloxy, 2-buten-1-yloxy,
3-buten-1-yloxy, methallyloxy, 2-penten-1-yloxy, 3-penten-1-yloxy,
4-penten-1-yloxy, 1-methylbut-2-en-1-yloxy or 2-ethylprop-2-en-1-yloxy.

[0145] C6-C12-Aryl-C1-C4-alkoxy is an alkoxy radical
having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein,
wherein one hydrogen atom is replaced by a C6-C12-aryl group as
defined herein. Examples include benzyloxy.

[0146] C1-C6-Alkylsulfonylamino-C1-C4-alkoxy is an
alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as
defined herein, wherein one hydrogen atom is replaced by an
alkylsulfonylamino group having from 1 to 6, preferably from 1 to 4
carbon atoms as defined herein. Examples include
2-(methylsulfonylamino)ethoxy, 2-(ethylsulfonylamino)ethoxy,
2-[(2-methylpropyl)sulfonylamino]ethoxy.

[0147] (Halogenated
C1-C6-alkyl)sulfonylamino-C1-C4-alkoxy is an alkoxy
radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined
herein, wherein one hydrogen atom is replaced by an alkylsulfonylamino
group having from 1 to 6, preferably from 1 to 4 carbon atoms as defined
herein, wherein the alkyl group is halogenated. Examples include
2-(trifluoromethylsulfonylamino)ethoxy.

[0148] C6-C12-Arylsulfonylamino-C1-C4-alkoxy is an
alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as
defined herein, wherein one hydrogen atom is replaced by a
C6-C12-arylsulfonylamino group as defined herein. Examples
include 2-(phenylsulfonylamino)-ethoxy, 2-(naphthylsulfonylamino)ethoxy.

[0149] (C6-C12-Aryl-C1-C6-alkyl)sulfonylamino-C1--
C4-alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2
carbon atoms as defined herein, wherein one hydrogen atom is replaced by
a (C6-C12-aryl-C1-C6-alkyl)sulfonylamino group,
preferably by a
(C6-C12-aryl-C1-C2-alkyl)sulfonylamino group.
Examples include 2-(benzylsulfonylamino)ethoxy.

[0150] C3-C12-Heterocyclylsulfonylamino-C1-C4-alkoxy
is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms
as defined herein, wherein one hydrogen atom is replaced by a
C3-C12-heterocyclylsulfonylamino group as defined herein.
Examples include 2-(pyridin-3-yl-sulfonylamino)ethoxy.

[0151] C3-C12-Heterocyclyl-C1-C4-alkoxy is an alkoxy
radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined
herein, wherein one hydrogen atom is replaced by a
C3-C12-heterocyclyl group as defined herein. Examples include
2-(N-pyrrolidinyl)ethoxy, 2-(N-morpholinyl)ethoxy and
2-(N-imidazolyl)ethoxy.

[0152] C1-C2-Alkylenedioxo is a radical of the formula
--O--R--O--, wherein R is a straight-chain or branched alkylene group
having from 1 or 2 carbon atoms as defined herein. Examples include
methylenedioxo.

[0153] C6-C12-Aryloxy is a radical of the formula R--O--,
wherein R is an aryl group having from 6 to 12, in particular 6 carbon
atoms as defined herein. Examples include phenoxy.

[0154] C3-C12-Heterocyclyloxy is a radical of the formula
R--O--, wherein R is a C3-C12-heterocyclyl group having from 3
to 12, in particular from 3 to 7 carbon atoms as defined herein. Examples
include pyridin-2-yloxy.

[0159] (Halogenated C1-C6-alkyl)sulfonyl is a
C1-C6-alkylsulfonyl as defined herein, wherein at least one,
e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4
or a corresponding number of identical or different halogen atoms.

[0160] C6-C12-Arylsulfonyl is a radical of the formula
R--S(O)2--, wherein R is an aryl radical having from 6 to 12 carbon
atoms as defined herein. Examples include phenylsulfonyl.

[0161] (C6-C12-Aryl-C1-C4-alkyl)sulfonyl is a radical
of the formula R--S(O)2--, wherein R is a
C6-C12-aryl-C1-C4-alkyl radical, in particular a
C6-C12-aryl-C1-C2-alkyl radical as defined herein.
Examples include benzylsulfonyl.

[0162] C3-C12-Heterocyclylsulfonyl is a radical of the formula
R--S(O)2--, wherein R is C3-C12-heterocyclyl as defined
herein.

[0163] Aminosulfonyl is NH2--S(O)2--.

[0164] C1-C6-Alkylaminosulfonyl is a radical of the formula
R--NH--S(O)2-- wherein R is an alkyl radical having from 1 to 6,
preferably from 1 to 4 carbon atoms as defined herein. Examples include
methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl,
iso-propylaminosulfonyl, n-butylaminosulfonyl, 2-butylaminosulfonyl,
iso-butylaminosulfonyl, tert-butylaminosulfonyl.

[0165] Di-C1-C6-alkylaminosulfonyl is a radical of the formula
RR'N--S(O)2-- wherein R and R' are independently of each other an
alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as
defined herein. Examples include dimethylaminosulfonyl,
diethylaminosulfonyl, N-methyl-N-ethylaminosulfonyl.

[0166] C6-C12-Arylaminosulfonyl is a radical of the formula
R--NH--S(O)2-- wherein R is an aryl radical having from 6 to 12,
preferably 6 carbon atoms as defined herein.

[0167] Amino is NH2.

[0168] C1-C6-Alkylamino is a radical of the formula R--NH--
wherein R is an alkyl radical having from 1 to 6, in particular from 1 to
4 carbon atoms as defined herein. Examples include methylamino,
ethylamino, n-propylamino, iso-propylamino, n-butylamino, 2-butylamino,
iso-butylamino, tert-butylamino.

[0169] (Halogenated C1-C6-alkyl)amino is a
C1-C6-alkylamino as defined herein, wherein at least one, e.g.
1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a
corresponding number of identical or different halogen atoms.

[0170] Di-C1-C6-alkylamino is a radical of the formula RR'N--
wherein R and R' are independently of each other an alkyl radical having
from 1 to 6, in particular from 1 to 4 carbon atoms as defined herein.
Examples include dimethylamino, diethylamino, N-methyl-N-ethylamino.

[0171] Di-(halogenated C1-C6-alkyl)amino is a
di-C1-C6-alkylamino as defined herein, wherein at least one,
e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4
or a corresponding number of identical or different halogen atoms.

[0172] C1-C6-Alkylcarbonylamino is a radical of the formula
R--C(O)--NH--, wherein R is an alkyl radical having from 1 to 6, in
particular from 1 to 4 carbon atoms as defined herein. Examples include
acetamido (methylcarbonylamino), propionamido, n-butyramido,
2-methylpropionamido (isopropylcarbonylamino), 2,2-dimethylpropionamido
and the like.

[0173] (Halogenated C1-C6-alkyl)carbonylamino is a
C1-C6-alkylcarbonylamino as defined herein, wherein at least
one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2,
3, 4 or a corresponding number of identical or different halogen atoms.

[0174] C6-C12-Arylcarbonylamino is a radical of the formula
R--C(O)--NH--, wherein R is an aryl radical having from 6 to 12 carbon
atoms as defined herein. Examples include phenylcarbonylamino.

[0175] C2-C6-Alkenylamino is a radical of the formula R--NH--,
wherein R is a straight-chain or branched alkenyl group having from 2 to
6, in particular 2 to 4 carbon atoms. Examples include vinylamino,
allylamino (2-propen-1-ylamino), 1-propen-1-ylamino, 2-propen-2-ylamino,
methallylamino (2-methylprop-2-en-1-ylamino) and the like.
C3-C5-Alkenylamino is, in particular, allylamino,
1-methylprop-2-en-1-ylamino, 2-buten-1-ylamino, 3-buten-1-ylamino,
methallylamino, 2-penten-1-ylamino, 3-penten-1-ylamino,
4-penten-1-ylamino, 1-methylbut-2-en-1-ylamino or
2-ethylprop-2-en-1-ylamino.

[0176] C1-C6-Alkylsulfonylamino is a radical of the formula
R--S(O)2--NH--, wherein R is an alkyl radical having from 1 to 6, in
particular from 1 to 4 carbon atoms as defined herein. Examples include
methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino,
iso-propylsulfonylamino, n-butylsulfonylamino, 2-butylsulfonylamino,
iso-butylsulfonylamino, tert-butylsulfonylamino.

[0177] (Halogenated C1-C6 alkyl)sulfonylamino is a
C1-C6-alkylsulfonylamino as defined herein, wherein at least
one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2,
3, 4 or a corresponding number of identical or different halogen atoms.

[0178] C6-C12-Arylsulfonylamino is a radical of the formula
R--S(O)2--NH--, wherein R is an aryl radical having from 6 to 12
carbon atoms as defined herein. Examples include phenylsulfonylamino.

[0179] Nitro is --NO2.

[0180] C3-C12-Heterocyclyl is a 3- to 12-membered heterocyclic
radical including a saturated heterocyclic radical, which generally has
3, 4, 5, 6, or 7 ring forming atoms (ring members), an unsaturated
non-aromatic heterocyclic radical, which generally has 5, 6 or 7 ring
forming atoms, and a heteroaromatic radical (hetaryl), which generally
has 5, 6 or 7 ring forming atoms. The heterocyclic radicals may be bound
via a carbon atom (C-bound) or a nitrogen atom (N-bound). Preferred
heterocyclic radicals comprise 1 nitrogen atom as ring member atom and
optionally 1, 2 or 3 further heteroatoms as ring members, which are
selected, independently of each other from O, S and N. Likewise preferred
heterocyclic radicals comprise 1 heteroatom as ring member, which is
selected from O, S and N, and optionally 1, 2 or 3 further nitrogen atoms
as ring members.

[0194] Heterocyclyl also includes bicyclic heterocycles, which comprise
one of the described 5- or 6-membered heterocyclic rings and a further
anellated, saturated or unsaturated or aromatic carbocycle, such as a
benzene, cyclohexane, cyclohexene or cyclohexadiene ring, or a further
anellated 5- or 6-membered heterocyclic ring, this heterocyclic ring
being saturated or unsaturated or aromatic. These include quinolinyl,
isoquinolinyl, indolyl, indolizinyl, isoindolyl, indazolyl, benzofuryl,
benzthienyl, benzo[b]thiazolyl, benzoxazolyl, benzthiazolyl and
benzimidazolyl. Examples of 5- or 6-membered heteroaromatic compounds
comprising an anellated cycloalkenyl ring include dihydroindolyl,
dihydroindolizinyl, dihydroisoindolyl, dihydroquinolinyl,
dihydroisoquinolinyl, chromenyl and chromanyl.

[0195] C3-C12-Heteroarylene is a heteroaryl diradical. Examples
include pyrid-2,5-ylene and pyrid-2,4-ylene.

[0197] In said formula (I) or (II), there may be one or more than one
substituent R2 and/or R6. More particularly, there may be up to
3 substituents R2 in formula (I) or (II), and up to 7 substituents
R6 (including R6 as a substituent of X1 if X1 is
>CH2 and including R6 as a substituent of X4 if X4
is >CH2) and up to 6 substituents R6 in formula (II).
Preferably there are 1 or 2 substituents R2 and/or 1 or 2
substituents R6. Formulae (I) and (II) may thus be depicted as
follows:

##STR00011##

wherein a is 1, 2, or 3 and b is 1, 2, 3, 4, 5, 6 or 7 (in formula (I) or
1, 2, 3, 4, 5 or 6 (in formula (I). If there is more than one radical
R2, these may be the same or different radicals. If there is more
than one radical R6, these may be the same or different radicals.

[0201] In connection with R1, substituted C6-C12-aryl in
particular includes C6-C12-aryl, such as phenyl or naphthyl,
substituted with 1, 2 or 3 substituents selected from the group
consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl,
cyano, C1-C4-alkoxy, C1-C4-haloalkoxy, amino,
C1-C4-alkylamino, C1-C4-dialkylamino, morpholino and
piperidinyl. The same applies to substituted C6-C12-aryl in
substituted C6-C12-aryl-C1-C4-alkyl.

[0202] In connection with R1, substituted
C3-C12-heterocyclyl in particular includes
C3-C12-heterocyclyl, such as pyridyl, thienyl, diazolyl,
quinolinyl, piperidinyl, piperazinyl or morpholinyl, pyrrolyl, isoxazolyl
and triazolyl being further examples of such
C3-C12-heterocyclyl, substituted with 1, 2 or 3 substituents
selected from the group consisting of halogen, C1-C4-alkyl,
C1-C4-haloalkyl, C1-C4-alkoxycarbonyl, cyano,
C1-C4-alkoxy, C1-C4-haloalkoxy,
C1-C4-alkylsulfonyl, amino, C1-C4-alkylamino,
C1-C4-dialkylamino, C6-C12-arylamino and
C3-C12-heterocyclyl (e.g., morpholino or piperidinyl). The same
applies to substituted C3-C12-heteroaryl in substituted
C3-C12-heteroaryl-C1-C4-alkyl.

[0203] According to one embodiment, W is --NR8-- and Y is a bond.
According to an alternative embodiment, W is a bond and Y is
--NR9--. According to a further alternative embodiment, W is a bond
and Y is a bond, especially if R1 is a nitrogen-bound radical, e.g.
nitrogen-bound heterocyclyl such as piperazinyl or morpholinyl.

[0204] According to one embodiment, Q is --S(O)2--. According to an
alternative embodiment, Q is --C(O)--.

[0205] According to a particular embodiment, --W-A1-Q-Y-- is
--W-A1-S(O)2--NR9--, --NR8--S(O)2--,
S(O)2-- or --S(O)2--. According to a further particular
embodiment, --W-A1-Q-Y-- is --W-A1-CO--NR9-- or
--NR8--CO--.

[0206] According to a particular embodiment, --W-A1-Q- is
--W-A1-S(O)2--, --NR8--S(O)2--, -A1-S(O)2--
or --S(O)2--. According to a further particular embodiment,
--W-A1-Q- is --W-A1-CO-- or --NR8--CO--.

[0207] A1 is optionally substituted C1-C4-alkylene or a
bond. In connection with A1, substituted C1-C4-alkylene in
particular includes C1-C4-alkylene substituted with 1, 2 or 3
substituents selected from the group consisting of halogen,
C1-C4-alkyl and cyano. Preferably, A1 is a bond. If
A1 is C1-C4-alkylene, W is preferably --NR8--.

[0208] A2 is optionally substituted C1-C4-alkylene (e.g.
methylene, 1,2-ethylene or 1,3-propylene), C1-C4-alkylene-CO--,
--CO--C1-C4-alkylene,
C1-C4-alkylene-O--C1-C4-alkylene,
C1-C4-alkylene-NR10--C1-C4-alkylene, optionally
substituted C6-C12-arylene, optionally substituted
C6-C12-heteroarylene or a bond. Additionally, A2 may be
optionally substituted C2-C4-alkenylene or optionally
substituted C2-C4-alkynylene. Preferably, A2 is optionally
substituted C1-C4-alkylene (e.g. methylene, 1,2-ethylene or
1,3-propylene). More preferably, A2 is C1-C4-alkylene
(e.g. methylene). Alternatively, it is preferred that A2 is
optionally substituted C6-C12-arylene, in particular
C6-C12-arylene selected from the group consisting of
phen-1,4-ylene and phen-1,3-ylene, or optionally substituted
C6-C12-heteroarylene, in particular
C6-C12-heteroarylene selected from the group consisting of
pyrid-2,5-ylene and pyrid-2,4-ylene. If A2 is a bond, X1 is
preferably >CH2.

[0209] In connection with A2, substituted C1-C4-alkylene in
particular includes C1-C4-alkylene substituted with 1, 2 or 3
substituents selected from the group consisting of halogen,
C1-C4-alkyl, C1-C4-haloalkyl and cyano.

[0210] In connection with A2, substituted C2-C4-alkenylene
or substituted C2-C4-alkynylene in particular includes
C2-C4-alkenylene or C2-C4-alkynylene substituted with
1, 2 or 3 substituents selected from the group consisting of halogen,
C1-C4-alkyl, C1-C4-haloalkyl and cyano.

[0214] According to a particular embodiment, A2 is a bond and X1
is >CH2.

[0215] According to a particular embodiment,
R1--W-A1-Q-Y-A2-X1-- is
R1--S(O)2--NH-A2-X1--,
R1--NH--S(O)2-A2-X1--,
R1--C(O)--NH-A2-X1-- or
R1--NH--C(O)-A2-X1--.

[0216] According to a particular embodiment, the structural element
--Y-A2- comprises at least 1 or 2 atoms in the main chain. According
to further particular embodiments the structural element --Y-A2- has
up to 2, 3 or 4 atoms in the main chain, such as 1 to 4, 1 to 3, or 1 to
2 atoms in the main chain, or especially 1 or 2 atoms in the main chain.

[0217] According to a further particular embodiment, --Y-A2- is
--NR9--C1-C4-alkylene- (e.g. --NH--CH2--,
--NH--(CH2)2-- or --NH--(CH2)3--), with --Y-A2-
preferably having 1 to 4, or 1 to 3, or especially 1 or 2 atoms in the
main chain. In this particular embodiment, R9 is as defined herein
and preferably R9 is hydrogen, C1-C6-alkyl (e.g. methyl or
ethyl) or C3-C12-cycloalkyl (e.g. cyclopropyl).

[0218] According to a further particular embodiment, --Y-A2- is
--C1-C4-alkylene- (e.g. --CH2--), with --Y-A2
preferably having 1 to 4, or 1 to 3, or especially 1 or 2 atoms in the
main chain.

[0219] According to a further particular embodiment, the structural motif
--Y-A2- as disclosed herein is bound to Q being --S(O)2-- or
--C(O)--. Particular examples for this embodiment include phenalkylamine
derivatives of the invention wherein R is R1--S(O)2--Y-A2-
or R1--C(O)--Y-A2-.

[0220] X4 is --O--, --NR19--, --S--, or >CH2. According
to a particular embodiment, X4 is --O-- or --NR19--.

[0221] In the phenalkylamine derivatives of formula (I), n is zero, 1 or
2. According to a particular embodiment, n is 1.

[0222] In the phenalkylamine derivatives of formula (II), m is zero, 1 or
2. According to a particular embodiment, m is 1 or 2.

[0223] According to a particular embodiment, the phenalkylamine
derivatives of formula (I) have one of the following formulae:

[0230] On the saturated ring, the phenalkylamine derivatives of the
invention may be substituted with one or more than one radical R6.
If there is more than one radical R6, these may be the same or
different radicals. The phenalkylamine derivatives of the invention may
therefore be represented by the following formula:

[0231] R6 is hydrogen, halogen, C1-C6-alkyl,
C1-C6-alkoxy, or two radicals R6 together with the carbon
atom to which they are attached form a carbonyl group.

[0232] Preferably, R6 is hydrogen or C1-C6-alkyl. In
particular, R6 is hydrogen.

[0233] In addition to the alkylamine moiety, the phenalkylamine
derivatives of the invention may have one or more than one further
substituent bound to the benzene ring. In these positions, the skeleton
of the phenalkylamine derivatives may thus be substituted with one or
more than one radical R2. If there is more than one radical R2,
these may be the same or different radicals. The phenalkylamine
derivatives of the invention may therefore be represented by one of the
following formulae:

[0235] An optionally substituted 5- or 6-membered ring that is formed by
two radicals R2 together with the ring atoms of the benzene ring to
which they are bound is, for instance, a benzene ring.

[0236] In connection with R2, substituted C6-C12-aryl in
particular includes C6-C12-aryl, such as phenyl, substituted
with 1, 2 or 3 substituents selected from the group consisting of halogen
and C1-C4-alkyl, C1-C4-haloalkyl, cyano,
C1-C4-alkoxy and C1-C4-haloalkoxy.

[0237] In connection with R2, substituted
C3-C12-heterocyclyl in particular includes
C3-C12-heterocyclyl, such as morpholinyl, pyrrolidinyl and
piperidinyl, substituted with 1, 2 or 3 substituents selected from the
group consisting of halogen, C1-C4-alkyl,
C1-C4-haloalkyl, cyano, C1-C4-alkoxy and
C1-C4-haloalkoxy.

[0238] Preferably, R2 is hydrogen, halogen or C1-C6-alkoxy.
In particular, R2 is hydrogen or halogen.

[0239] According to a particular embodiment, the phenalkylamine
derivatives of the invention have one of the following formulae:

[0246] In connection with R12a and R13a, substituted
C1-C6-alkyl in particular includes C1-C6-alkyl
substituted with 1, 2 or 3 substituents selected from the group
consisting of halogen, hydroxy, C1-C4-alkoxy and amino.

[0247] In connection with R12a and R13a, substituted
C6-C12-aryl in particular includes C6-C12-aryl, such
as phenyl, substituted with 1, 2 or 3 substituents selected from the
group consisting of C1-C4-alkyl, C1-C4-haloalkyl,
cyano, C1-C4-alkoxy and C1-C4-haloalkoxy.

[0248] R12b is hydrogen or C1-C6-alkyl. According to a
particular embodiment, R12b is hydrogen.

[0249] R13b is hydrogen or C1-C6-alkyl. According to a
particular embodiment, R13b is hydrogen.

[0250] Alternatively, R12a and R12b, or R13a and R13b,
together are together are carbonyl or, preferably, optionally substituted
C1-C4-alkylene (e.g. 1,3-propylene), wherein one --CH2--
of C1-C4-alkylene may be replaced by an oxygen atom or
--NR17-- or NR18.

[0251] In connection with R12a and R12b, or R13a and
R13b, substituted C1-C4-alkylene in particular includes
C1-C4-alkylene substituted with 1, 2 or 3 substituents selected
from the group consisting of halogen, C1-C4-alkyl,
C1-C4-haloalkyl, cyano, C1-C4-alkoxy and
C1-C4-haloalkoxy.

[0252] According to a particular embodiment, R12a is
C1-C6-alkyl and R12b is hydrogen or C1-C6-alkyl,
or R13a is C1-C6-alkyl and R13b is hydrogen or
C1-C6-alkyl.

[0253] According to a further particular embodiment, R12a is hydrogen
and R12b is hydrogen, or R13a is hydrogen and R13b is
hydrogen.

[0254] According to a further particular embodiment, R12a and
R12b together are optionally substituted 1,3-propylene, or R13a
and R13b together are optionally substituted 1,3-propylene.

[0277] According to a particular embodiment, R15a is hydrogen and
R15b is hydrogen.

[0278] Alternatively, R15a, R15b together are carbonyl or
optionally substituted C1-C4-alkylene, wherein one or two
--CH2-- of C1-C4-alkylene may be replaced by an oxygen
atom or --NR20--.

[0279] In connection with R14a and R14b, or R15a and
R15b, substituted C1-C4-alkylene in particular includes
C1-C4-alkylene substituted with 1, 2 or 3 substituents selected
from the group consisting of halogen, C1-C4-alkyl,
C1-C4-haloalkyl, cyano, C1-C4-alkoxy and
C1-C4-haloalkoxy.

[0283] Alternatively, R4a and R3 together are optionally
substituted C1-C4-alkylene (e.g. methylene or 1,2 ethylene, a
further example being 1,3-propylene, 1-oxo-1,2-ethylene,
1-oxo-1,3-propylene) so that R4a and R3 together with the
--Y1--Y2--N-- moiety and the C atom to which R3 is bound
form an heterocyclic ring having, in particular, 4, 5, or 6 ring member
atoms (including the nitrogen atom). With R4a and R3 together
being optionally substituted C1-C4-alkylene, such
phenalkylamine derivatives may be represented by the following partial
structure:

[0284] In connection with R4a and R3, substituted
C1-C4-alkylene in particular includes C1-C4-alkylene
substituted with 1, 2 or 3 substituents selected from the group
consisting of halogen (e.g. fluoro), C1-C4-alkyl or oxo.

[0285] Alternatively, Y1 is >CR14aR14b and R4a and
R14a together are optionally substituted C1-C4-alkylene
(e.g. methylene) so that R4a and R14a together with the
--C(R14b)--Y2--N-- moiety is bound form an heterocyclic ring
having, in particular, 4, 5, or 6 ring member atoms (including the
nitrogen atom). With R4a and R14a together being
C1-C4-alkylene, such a ring may be represented by the following
partial structure:

[0286] In connection with R4a and R14a, substituted
C1-C4-alkylene in particular includes C1-C4-alkylene
substituted with 1, 2 or 3 substituents selected from the group
consisting of halogen (e.g. fluoro), C1-C4-alkyl and oxo.

[0289] Alternatively, R4a, R4b together are optionally
substituted C1-C6-alkylene (e.g. 1,4-butylene, 1,3-propylene,
2-fluoro-but-1,4-ylene or 1-oxo-but-1,4-ylene), wherein one --CH2--
of C1-C6-alkylene may be replaced by an oxygen atom (e.g.
--CH2--CH2--O--CH2--CH2--) or --NR16.

[0290] In connection with R4a and R4b, substituted
C1-C6-alkylene in particular includes C1-C6-alkylene
substituted with 1, 2 or 3 substituents selected from the group
consisting of halogen (e.g. fluoro or chloro), C1-C4-alkyl,
cyano, hydroxy and C1-C4-alkoxy.

[0294] According to a particular embodiment, R9 and R1 together
are C1-C4-alkylene (e.g. 1,3-1,2-ethylene or propylene) so as
that R9 and R1 together with the atom in Q to which R1 is
bound and the nitrogen atom to which R9 is bound form an
heterocyclic ring having, in particular, 4, 5 or 6 ring member atoms
(including the nitrogen atom and Q). With W and A1 both being a
bond, such a ring may be represented by the following partial structure:

[0295] According to a further particular embodiment, R9 is
C1-C4-alkylene (e.g. methylene or 1,3-propylene) that is bound
to a carbon atom in A2 and A2 is C1-C4-alkylene so
that R9 and at least part of A2 together with the nitrogen atom
to which R9 is bound form an N-containing heterocyclic ring having,
in particular, 4, 5, 6 or 7 ring member atoms (including the nitrogen
atom). Such a ring may be represented by the following partial structure:

##STR00025##

wherein R1, W, A1 and Q are as defined herein, p is 1 or 2, r
is 0, 1 or 2 and q is 0, 1 or 2. In this particular embodiment, X1
preferably is --O--. Particular combinations of p, r and q include p=1,
r=0, q=1; and p=1, r=0, q=0. Alternatively, p is 0, r is 3 and q is 1,
with X1 preferably being --O--.

[0328] Particular embodiments of phenalkylamine derivatives of the
invention result if in formula (II) [0329] R1 is
C3-C12-cycloalkyl-C1-C4-alkyl (e.g.
cyclopropylmethyl), or optionally substituted
C3-C12-heterocyclyl (e.g. 1-methyl-1,2-diazol-4-yl or
1-methyl-1,3-diazol-4-yl); [0330] W is a bond; [0331] A1 is a bond;
[0332] Q is --S(O)2-- or --C(O)--; [0333] m is 2; [0334] R6 is
hydrogen; [0335] R2 is hydrogen; [0336] R3 is hydrogen; [0337]
X2 is >CR12aR12b; [0338] X3 is a bond; [0339]
R5 is phenyl; [0340] Y1 is a bond; [0341] Y2 is
>CR15aR15b; [0342] R4a is hydrogen or
C1-C6-alkyl (e.g. methyl); [0343] R4b is hydrogen or
C1-C6-alkyl (e.g. methyl); or [0344] R12a is hydrogen;
[0345] R12b is hydrogen; or [0346] R15a is hydrogen; and [0347]
R15b is hydrogen.

[0348] Particular compounds of the present invention are the
phenalkylamine derivatives disclosed in preparation examples and
physiologically tolerated salts thereof. These include for each
preparation example the exemplified compound as well as the corresponding
free base and any other physiologically tolerated salts of the free base
(if the exemplified compound is a salt), or any physiologically tolerated
salt of the free base (if the exemplified compound is a free base). These
further include enantiomers, diastereomers, tautomers and any other
isomeric forms of said compounds, be they explicitly or implicitly
disclosed.

[0350] The compounds of the formula (I) or (II) can be prepared by analogy
to methods which are well known in the art. Suitable methods for the
preparation of compounds of formula (I) or (II) are outlined in the
following schemes.

[0351] The compounds of the formula (I) can be prepared by analogy to
methods which are well known in the art. A suitable method for the
preparation of compounds of formula (I) is outlined in the following
schemes. The variables X1, X2, X3, X4, R2,
R6 are as defined herein, L1 represents a alkyl substituent
(e.g. Me, Et), L2 and L are suitable protecting groups (e.g.
L2=COOtBu and L=tBuMe2Si or Bn). The process depicted in scheme
1 is useful for obtaining phenalkylamines of the general formula 5,
wherein X1 is O and X4 is N.

##STR00026##

[0352] Compounds of the formula 2 can be obtained by substitution reaction
with 2,3-dibromopropionic acid derivatives to afford dihydrobenzoxazine
type structures of formula 2 (J. Med. Chem. 2006, 49, 7095, Bioorg. &
Med, Chem. Letters 2006, 16, 1338). Bromination of the (e.g. methyl) side
chain and protection of the aniline leads to structure 4. Subsequent
reduction of the ester leads to alcohols of formula 5, which can be
protected by suitable protecting group L (e.g. L=tBuMe2Si or Bn).

[0353] The process depicted in scheme 2 is useful for obtaining rigid
phenalkylamines, wherein the variables X1, X2, X3,
X4, R5 are as defined herein, L is a suitable protecting group
(e.g. COOtBu), and L1 represents a free carboxylic acid or a
corresponding ester (e.g. H, Me, Et, alkyl). Compounds of the general
formula 7 wherein X1 and X4 is O e.g. are well described in the
literature and often commercially available.

##STR00027##

[0354] As shown in scheme 2, the compound of general formula 7 can easily
be reduced to give the compound of general formula 8 by common reducing
agents (e.g. borane complexes). Conversion to the corresponding bromide
via a standard substitution protocol (e.g. PBr3 in presence of a
base like Et3N) leads to formula 9. The nitrile 10 can be obtained
by a subsequent substitution with a cyanide salt (e.g. NaCN). A
subsequent aldol-type condensation reaction in presence of a base (e.g.
NaOEt) and a suitable aldehyde (e.g. benzaldehyde) followed by reduction
of the initially formed double bond affords rigid phenalkylamines of
formula 11. Compound 11 can be further converted to compounds of formula
12 by a deprotection step. As described above, a standard substitution
protocol with a bromine source (e.g. PBr3 in the presence of a base
like Et3N) can yield bromides of formula 13, which can easily be
transformed into the amines of formula 14 via an azide substitution
followed by PPh3 reduction (Staudinger-protocol, Bioorg. & Med.
Chem. Letters 2006, 16, 1338). Reaction with sulfonyl chlorides leads to
the corresponding sulfonamides of formula 15. Compounds of the general
formula 16 can be obtained by reduction of the nitrile (e.g. borane
complexes, Raney-Ni).

[0355] The process depicted in scheme 3 is useful for obtaining rigid
phenalkylamines, wherein Y is a bond, A2 is CH2 and Q is
SO2 (Journal of Organic Chemistry 1985, 50, 5184).

##STR00028##

[0356] Starting from compound of formula 13 the corresponding thio ethers
17 can be obtained by substitution of the bromide by a suitable sulfur
nucleophile (e.g. sodium thiolates). Oxidation to the sulfones of formula
18 can be achieved by state of the art procedures (e.g. NalO4,
oxone, KMnO4, meta-chlorobenzoic acid). Compounds of the general
formula 19 can then be obtained via reduction procedures as describes
above (scheme 2).

[0357] The process depicted in scheme 4 is useful for obtaining rigid
phenalkylamines, wherein Y and A1 are bonds, A2 is CH2, Q
is SO2 and W is N.

##STR00029##

[0358] Starting from compounds of formula 13 the corresponding
sulfonylchlorides 20 can be obtained as described in the literature (Org.
& Bioorg. Chem. 2007, 51, 1093). Sulfonamides can be obtained by state of
the art reaction with a suitable amine to give compound 21, which can be
further transformed into compounds of the formula 22 via reduction
procedures as describes above (scheme 2).

Formula (II)

[0359] The compounds of the formula (II) can be prepared by analogy to
methods which are well known in the art. A suitable method for the
preparation of compounds of formula (II) is outlined in the following
schemes. The variables X2, X3, R5 are as defined herein
and L is a suitable protecting group (e.g. L=COOtBu).

[0361] As shown in scheme 5, the compound of general formula 23 can easily
be reduced to give the compound of general formula 24 by common reducing
agents (e.g. borane complexes). Conversion to the corresponding bromide
via standard substitution protocol (e.g. PBr3 in presence of a base
like Et3N) leads to formula 25. The nitrile 26 can be obtained from
25 by a subsequent substitution with a cyanide salt (e.g. NaCN). A
subsequent aldol-type condensation reaction in presence of a base (e.g.
NaOEt) and a suitable aldehyde (e.g. benzaldehyde) followed by reduction
of the initially formed double bond affords rigid phenalkylamines of
formula 27. Compound 27 can be further converted to compounds of general
formula 32 as displayed in scheme 6.

[0362] The process depicted in scheme 6 is useful for obtaining
phenalkylamines of the formula II, wherein Q is --S(O)2.

[0364] As shown in the above scheme 6, the compound of general formula 28
readily undergoes cleavage of the suitable protecting group (e.g.
COOtBu). Sulfonylation under basic conditions (e.g. DMAP, pyridine)
affords compounds of the general formula 30. Subsequent reduction of the
nitrile to the corresponding amines 31 can be achieved using standard
protocols (e.g. borane complexes, Raney-Nickel, H2). Alkylation
leads to rigid phenalkylamines of general formula 32.

[0366] The compounds of the formula (I) or (II) are capable of inhibiting
the activity of glycine transporter, in particular glycine transporter 1
(GlyT1).

[0367] The utility of the compounds in accordance with the present
invention as inhibiting the glycine transporter activity, in particular
GlyT1 activity, may be demonstrated by methodology known in the art. For
instance, human GlyT1c expressing recombinant hGlyT1c--5_CHO cells
can be used for measuring glycine uptake and its inhibition (IC50)
by a compound of formula (I) or (II).

[0368] Amongst the compounds of the formula (I) or (II) those are
preferred which achieve effective inhibition at low concentrations. In
particular, compounds of the formula (I) or (II) are preferred which
inhibit glycine transporter 1 (GlyT1) at a level of IC50<1
μMol, more preferably at a level of IC50<0.5 μMol,
particularly preferably at a level of IC50<0.2 μMol and most
preferably at a level of IC50<0.1 μMol.

[0369] The compounds of the formula (I) or (II) according to the present
invention are thus useful as pharmaceuticals.

[0370] The present invention therefore also relates to pharmaceutical
compositions which comprise an inert carrier and a compound of the
formula (I) or (II).

[0371] The present invention also relates to the use of the compounds of
the formula (I) or (II) in the manufacture of a medicament for inhibiting
the glycine transporter GlyT1, and to corresponding methods of inhibiting
the glycine transporter GlyT1.

[0372] The NMDA receptor is central to a wide range of CNS processes, and
its role in a variety of diseases in humans or other species has been
described. GlyT1 inhibitors slow the removal of glycine from the synapse,
causing the level of synaptic glycine to rise. This in turn increases the
occupancy of the glycine binding site on the NMDA receptor, which
increases activation of the NMDA receptor following glutamate release
from the presynaptic terminal. Glycine transport inhibitors and in
particular inhibitors of the glycine trans-porter GlyT1 are thus known to
be useful in treating a variety of neurologic and psychiatric disorders.
Further, glycine A receptors play a role in a variety of diseases in
humans or other species. Increasing extracellular glycine concentrations
by inhibiting glycine trans-port may enhance the activity of glycine A
receptors. Glycine transport inhibitors and in particular inhibitors of
the glycine transporter GlyT1 are thus useful in treating a variety of
neurologic and psychiatric disorders.

[0373] The present invention thus further relates to the use of the
compounds of the formula (I) or (II) for the manufacture of a medicament
for treating a neurologic or psychiatric disorder, and to corresponding
methods of treating said disorders.

[0374] According to a particular embodiment, the disorder is associated
with glycinergic or glutamatergic neurotransmission dysfunction.

[0376] According to a further particular embodiment, the disorder is pain,
in particular chronic pain and especially neuropathic pain.

[0377] Pain can be classified as acute and chronic pain. Acute pain and
chronic pain differ in their etiology, pathophysiology, diagnosis and
treatment.

[0378] Acute pain, which occurs following tissue injury, is self-limiting,
serves as an alert to ongoing tissue damage and following tissue repair
it will usually subside. There are minimal psychological symptoms
associated with acute pain apart from mild anxiety. Acute pain is
nociceptive in nature and occurs following chemical, mechanical and
thermal stimulation of A-delta and C-polymodal pain receptors.

[0379] Chronic pain, on the other hand, serves no protective biological
function. Rather than being the symptom of tissue damage it is a disease
in its own right. Chronic pain is unrelenting and not self-limiting and
can persist for years, perhaps decades after the initial injury. Chronic
pain can be refractory to multiple treatment regimes. Psychological
symptoms associated with chronic pain include chronic anxiety, fear,
depression, sleeplessness and impairment of social interaction. Chronic
non-malignant pain is predominantly neuropathic in nature and involves
damage to either the peripheral or central nervous systems.

[0380] Acute pain and chronic pain are caused by different
neuro-physiological processes and therefore tend to respond to different
types of treatments. Acute pain can be somatic or visceral in nature.
Somatic pain tends to be a well localised, constant pain and is described
as sharp, aching, throbbing or gnawing. Visceral pain, on the other hand,
tends to be vague in distribution, paroxysmal in nature and is usually
described as deep, aching, squeezing or colicky in nature. Examples of
acute pain include post-operative pain, pain associated with trauma and
the pain of arthritis. Acute pain usually responds to treatment with
opioids or non-steroidal anti-inflammatory drugs.

[0381] Chronic pain, in contrast to acute pain, is described as burning,
electric, tingling and shooting in nature. It can be continuous or
paroxysmal in presentation. The hallmarks of chronic pain are chronic
allodynia and hyperalgesia. Allodynia is pain resulting from a stimulus
that normally does not ellicit a painful response, such as a light touch.
Hyperalgesia is an increased sensitivity to normally painful stimuli.
Primary hyperalgesia occurs immediately within the area of the injury.
Secondary hyperalgesia occurs in the undamaged area surrounding the
injury. Examples of chronic pain include complex regional pain syndrome,
pain arising from peripheral neuropathies, post-operative pain, chronic
fatigue syndrome pain, tension-type headache, pain arising from
mechanical nerve injury and severe pain associated with diseases such as
cancer, metabolic disease, neurotropic viral disease, neurotoxicity,
inflammation, multiple sclerosis or any pain arising as a consequence of
or associated with stress or depressive illness.

[0382] Although opioids are cheap and effective, serious and potentially
life-threatening side effects occur with their use, most notably
respiratory depression and muscle rigidity. In addition the doses of
opioids which can be administered are limited by nausea, emesis,
constipation, pruritis and urinary retention, often resulting in patients
electing to receive sub-optimal pain control rather than suffer these
distressing side-effects. Furthermore, these side-effects often result in
patients requiring extended hospitalisation. Opioids are highly addictive
and are scheduled drugs in many territories.

[0387] Particular neurologic disorders that can be treated with the
compounds of the formula (I) or (II) include in particular a cognitive
disorder such as dementia, cognitive impairment, attention deficit
hyperactivity disorder.

[0388] Particular psychiatric disorders that can be treated with the
compounds of the formula (I) or (II) include in particular an anxiety
disorder, a mood disorder such as depression or a bipolar disorder,
schizophrenia, a psychotic disorder.

[0389] Within the context of the treatment, the use according to the
invention of the compounds of the formula (I) or (II) involves a method.
In this method, an effective quantity of one or more compounds or the
formula (I) or (II), as a rule formulated in accordance with
pharmaceutical and veterinary practice, is administered to the individual
to be treated, preferably a mammal, in particular a human being. Whether
such a treatment is indicated, and in which form it is to take place,
depends on the individual case and is subject to medical assessment
(diagnosis) which takes into consideration signs, symptoms and/or
malfunctions which are present, the risks of developing particular signs,
symptoms and/or malfunctions, and other factors.

[0390] As a rule, the treatment is effected by means of single or repeated
daily administration, where appropriate together, or alternating, with
other drugs or drug-containing preparations.

[0391] The invention also relates to the manufacture of pharmaceutical
compositions for treating an individual, preferably a mammal, in
particular a human being. Thus, the compounds of the formula (I) or (II)
are customarily administered in the form of pharmaceutical compositions
which comprise an inert carrier (e.g. a pharmaceutically acceptable
excipient) together with at least one compound according to the invention
and, where appropriate, other drugs. These compositions can, for example,
be administered orally, rectally, transdermally, subcutaneously,
intravenously, intramuscularly or intranasally.

[0392] Examples of suitable pharmaceutical formulations are solid
medicinal forms, such as powders, granules, tablets, in particular film
tablets, lozenges, sachets, cachets, sugar-coated tablets, capsules, such
as hard gelatin capsules and soft gelatin capsules, suppositories or
vaginal medicinal forms, semisolid medicinal forms, such as ointments,
creams, hydrogels, pastes or plasters, and also liquid medicinal forms,
such as solutions, emulsions, in particular oil-in-water emulsions,
suspensions, for example lotions, injection preparations and infusion
preparations, and eyedrops and eardrops. Implanted release devices can
also be used for administering inhibitors according to the invention. In
addition, it is also possible to use liposomes or microspheres.

[0393] When producing the compositions, the compounds according to the
invention are optionally mixed or diluted with one or more carriers
(excipients). Carriers (excipients) can be solid, semisolid or liquid
materials which serve as vehicles, carriers or medium for the active
compound.

[0395] The compounds of formula (I) or (II) may also be suitable for
combination with other therapeutic agents.

[0396] Thus, the present invention also provides:

i) a combination comprising a compound of formula (I) or (II) with one or
more further therapeutic agents; ii) a pharmaceutical composition
comprising a combination product as defined in i) above and at least one
carrier, diluent or excipient; iii) the use of a combination as defined
in i) above in the manufacture of a medicament for treating or preventing
a disorder, disease or condition as defined herein; iv) a combination as
defined in i) above for use in treating or preventing a disorder, disease
or condition as defined herein; v) a kit-of-parts for use in the
treatment of a disorder, disease or condition as defined herein,
comprising a first dosage form comprising a compound of formula (I) or
(II) and one or more further dosage forms each comprising one or more
further therapeutic agents for simultaneous therapeutic administration,
vi) a combination as defined in i) above for use in therapy; vii) a
method of treatment or prevention of a disorder, disease or condition as
defined herein comprising administering an effective amount of a
combination as defined in i) above; viii) a combination as defined in i)
above for treating or preventing a disorder, disease or condition as
defined herein.

[0397] The combination therapies of the invention may be administered
adjunctively. By adjunctive administration is meant the coterminous or
overlapping administration of each of the components in the form of
separate pharmaceutical compositions or devices. This regime of
therapeutic administration of two or more therapeutic agents is referred
to generally by those skilled in the art and herein as adjunctive
therapeutic administration; it is also known as add-on therapeutic
administration. Any and all treatment regimes in which a patient receives
separate but coterminous or overlapping therapeutic administration of the
compounds of formula (I) or (II) and at least one further therapeutic
agent are within the scope of the current invention. In one embodiment of
adjunctive therapeutic administration as described herein, a patient is
typically stabilised on a therapeutic administration of one or more of
the components for a period of time and then receives administration of
another component.

[0398] The combination therapies of the invention may also be administered
simultaneously. By simultaneous administration is meant a treatment
regime wherein the individual components are administered together,
either in the form of a single pharmaceutical composition or device
comprising or containing both components, or as separate compositions or
devices, each comprising one of the components, administered
simultaneously. Such combinations of the separate individual components
for simultaneous combination may be provided in the form of a
kit-of-parts.

[0399] In a further aspect, the invention provides a method of treatment
of a psychotic disorder by adjunctive therapeutic administration of
compounds of formula (I) or (II) to a patient receiving therapeutic
administration of at least one antipsychotic agent. In a further aspect,
the invention provides the use of compounds of formula (I) or (II) in the
manufacture of a medicament for adjunctive therapeutic administration for
the treatment of a psychotic disorder in a patient receiving therapeutic
administration of at least one antipsychotic agent. The invention further
provides compounds of formula (I) or (II) for use for adjunctive
therapeutic administration for the treatment of a psychotic disorder in a
patient receiving therapeutic administration of at least one
antipsychotic agent.

[0400] In a further aspect, the invention provides a method of treatment
of a psychotic disorder by adjunctive therapeutic administration of at
least one antipsychotic agent to a patient receiving therapeutic
administration of compounds of formula (I) or (II). In a further aspect,
the invention provides the use of at least one antipsychotic agent in the
manufacture of a medicament for adjunctive therapeutic administration for
the treatment of a psychotic disorder in a patient receiving therapeutic
administration of compounds of formula (I) or (II). The invention further
provides at least one antipsychotic agent for adjunctive therapeutic
administration for the treatment of a psychotic disorder in a patient
receiving therapeutic administration of compounds of formula (I) or (II).

[0401] In a further aspect, the invention provides a method of treatment
of a psychotic disorder by simultaneous therapeutic administration of
compounds of formula (I) or (II) in combination with at least one
antipsychotic agent. The invention further provides the use of a
combination of compounds of formula (I) or (II) and at least one
antipsychotic agent in the manufacture of a medicament for simultaneous
therapeutic administration in the treatment of a psychotic disorder. The
invention further provides a combination of compounds of formula (I) or
(II) and at least one antipsychotic agent for simultaneous therapeutic
administration in the treatment of a psychotic disorder. The invention
further provides the use of compounds of formula (I) or (II) in the
manufacture of a medicament for simultaneous therapeutic administration
with at least one antipsychotic agent in the treatment of a psychotic
disorder. The invention further provides compounds of formula (I) or (II)
for use for simultaneous therapeutic administration with at least one
antipsychotic agent in the treatment of a psychotic disorder. The
invention further provides the use of at least one antipsychotic agent in
the manufacture of a medicament for simultaneous therapeutic
administration with compounds of formula (I) or (II) in the treatment of
a psychotic disorder. The invention further provides at least one
antipsychotic agent for simultaneous therapeutic administration with
compounds of formula (I) or (II) in the treatment of a psychotic
disorder.

[0402] In further aspects, the invention provides a method of treatment of
a psychotic disorder by simultaneous therapeutic administration of a
pharmaceutical composition comprising compounds of formula (I) or (II)
and at least one mood stabilising or antimanic agent, a pharmaceutical
composition comprising compounds of formula (I) or (II) and at least one
mood stabilising or antimanic agent, the use of a pharmaceutical
composition comprising compounds of formula (I) or (II) and at least one
mood stabilising or antimanic agent in the manufacture of a medicament
for the treatment of a psychotic disorder, and a pharmaceutical
composition comprising compounds of formula (I) or (II) and at least one
mood stabilising or antimanic agent for use in the treatment of a
psychotic disorder.

[0403] Antipsychotic agents include both typical and atypical
antipsychotic drugs. Examples of antipsychotic drugs that are useful in
the present invention include, but are not limited to: butyrophenones,
such as haloperidol, pimozide, and droperidol; phenothiazines, such as
chlorpromazine, thioridazine, mesoridazine, trifluoperazine,
perphenazine, fluphenazine, thiflupromazine, prochlorperazine, and
acetophenazine; thioxanthenes, such as thiothixene and chlorprothixene;
thienobenzodiazepines; dibenzodiazepines; benzisoxazoles;
dibenzothiazepines; imidazolidinones; benziso-thiazolyl-piperazines;
triazine such as lamotrigine; dibenzoxazepines, such as loxapine;
dihydroindolones, such as molindone; aripiprazole; and derivatives
thereof that have antipsychotic activity.

[0404] Examples of tradenames and suppliers of selected antipsychotic
drugs are as follows: clozapine (available under the tradename
CLOZARIL®, from Mylan, Zenith Goldline, UDL, Novartis); olanzapine
(available under the tradename ZYPREX®, from Lilly); ziprasidone
(available under the tradename GEODON®, from Pfizer); risperidone
(available under the tradename RISPERDAL®, from Janssen); quetiapine
fumarate (available under the tradename SEROQUEL®, from AstraZeneca);
haloperidol (available under the tradename HALDOL®, from
Ortho-McNeil); chlorpromazine (available under the tradename
THORAZINE®, from SmithKline Beecham (GSK)); fluphenazine (available
under the tradename PROLIXIN®, from Apothecon, Copley, Schering,
Teva, and American Pharmaceutical Partners, Pasadena); thiothixene
(available under the tradename NAVANE®, from Pfizer); trifluoperazine
(10-[3-(4-methyl-1-piperazinyl)propyl]-2-(trifluoromethyl)phenothiazine
dihydrochloride, available under the tradename STELAZINE®, from Smith
Klein Beckman); perphenazine (available under the tradename
TRILAFON®; from Schering); thioridazine (available under the
tradename MELLARIL®; from Novartis, Roxane, HiTech, Teva, and
Alpharma); molindone (available under the tradename MOBAN®, from
Endo); and loxapine (available under the tradename LOXITANE (D; from
Watson). Furthermore, benperidol (Glianimon®), perazine
(Taxilan®) or melperone (Eunerpan®) may be used. Other
antipsychotic drugs include promazine (available under the tradename
SPARINE®), triflurpromazine (available under the tradename VESPRI
N®), chlorprothixene (available under the tradename TARACTAN®),
droperidol (available under the tradename INAPSINE®), acetophenazine
(available under the tradename TINDAL®), prochlorperazine (available
under the tradename COMPAZINE®), methotrimeprazine (available under
the tradename NOZINAN®), pipotiazine (available under the tradename
PIPOTRIL®), ziprasidone, and hoperidone.

[0405] In a further aspect, the invention provides a method of treatment
of a neurodegenerative disorder such as Alzheimer Disease by adjunctive
therapeutic administration of compounds of formula (I) or (II) to a
patient receiving therapeutic administration of at least one agent
suitable for the treatment of a neurodegenerative disorder such as
Alzheimer Disease. In a further aspect, the invention provides the use of
compounds of formula (I) or (II) in the manufacture of a medicament for
adjunctive therapeutic administration for the treatment of a
neurodegenerative disorder such as Alzheimer Disease in a patient
receiving therapeutic administration of at least one agent suitable for
the treatment of a neurodegenerative disorder such as Alzheimer Disease.
The invention further provides compounds of formula (I) or (II) for use
for adjunctive therapeutic administration for the treatment of a
neurodegenerative disorder such as Alzheimer Disease in a patient
receiving therapeutic administration of at least one agent suitable for
the treatment of a neurodegenerative disorder such as Alzheimer Disease.

[0406] In a further aspect, the invention provides a method of treatment
of a neurodegenerative disorder such as Alzheimer Disease by adjunctive
therapeutic administration of at least one agent suitable for the
treatment of a neurodegenerative disorder such as Alzheimer Disease to a
patient receiving therapeutic administration of compounds of formula (I)
or (II). In a further aspect, the invention provides the use of at least
one agent suitable for the treatment of a neurodegenerative disorder such
as Alzheimer Disease in the manufacture of a medicament for adjunctive
therapeutic administration for the treatment of a neurodegenerative
disorder such as Alzheimer Disease in a patient receiving therapeutic
administration of compounds of formula (I) or (II). The invention further
provides at least one agent suitable for the treatment of a
neurodegenerative disorder such as Alzheimer Disease for adjunctive
therapeutic administration for the treatment of a neurodegenerative
disorder such as Alzheimer Disease in a patient receiving therapeutic
administration of compounds of formula (I) or (II).

[0407] In a further aspect, the invention provides a method of treatment
of a neurodegenerative disorder such as Alzheimer Disease by simultaneous
therapeutic administration of compounds of formula (I) or (II) in
combination with at least one agent suitable for the treatment of a
neurodegenerative disorder such as Alzheimer Disease. The invention
further provides the use of a combination of compounds of formula (I) or
(II) and at least one agent suitable for the treatment of a
neurodegenerative disorder such as Alzheimer Disease in the manufacture
of a medicament for simultaneous therapeutic administration in the
treatment of a neurodegenerative disorder such as Alzheimer Disease. The
invention further provides a combination of compounds of formula (I) or
(II) and at least one agent suitable for the treatment of a
neurodegenerative disorder such as Alzheimer Disease for simultaneous
therapeutic administration in the treatment of a neurodegenerative
disorder such as Alzheimer Disease. The invention further provides the
use of compounds of formula (I) or (II) in the manufacture of a
medicament for simultaneous therapeutic administration with at least one
agent suitable for the treatment of a neurodegenerative disorder such as
Alzheimer Disease in the treatment of a neurodegenerative disorder such
as Alzheimer Disease. The invention further provides compounds of formula
(I) or (II) for use for simultaneous therapeutic administration with at
least one agent suitable for the treatment of a neurodegenerative
disorder such as Alzheimer Disease in the treatment of a
neurodegenerative disorder such as Alzheimer Disease. The invention
further provides the use of at least one agent suitable for the treatment
of a neurodegenerative disorder such as Alzheimer Disease in the
manufacture of a medicament for simultaneous therapeutic administration
with compounds of formula (I) or (II) in the treatment of a
neurodegenerative disorder such as Alzheimer Disease. The invention
further provides at least one agent suitable for the treatment of a
neurodegenerative disorder such as Alzheimer Disease for simultaneous
therapeutic administration with compounds of formula (I) or (II) in the
treatment of a neurodegenerative disorder such as Alzheimer Disease.

[0409] Suitable cholinesterase inhibitors which may be used in combination
with the compounds of the inventions include for example tacrine,
donepezil, galantamine and rivastigmine.

[0410] Suitable NMDA receptors targeting agents which may be used in
combination with the compounds of the inventions include for example
memantine.

[0411] Suitable agents affecting increased HPA axis activity which may be
used in combination with the compounds of the inventions include for
example CRF1 antagonists or V1b antagonists.

[0412] In a further aspect therefore, the invention provides a method of
treatment of pain by adjunctive therapeutic administration of compounds
of formula (I) or (II) to a patient receiving therapeutic administration
of at least one agent suitable for the treatment of pain. In a further
aspect, the invention provides the use of compounds of formula (I) or
(II) in the manufacture of a medicament for adjunctive therapeutic
administration for the treatment of pain in a patient receiving
therapeutic administration of at least one agent suitable for the
treatment of pain. The invention further provides compounds of formula
(I) or (II) for use for adjunctive therapeutic administration for the
treatment of pain in a patient receiving therapeutic administration of at
least one agent suitable for the treatment of pain.

[0413] In a further aspect, the invention provides a method of treatment
of pain by adjunctive therapeutic administration of at least one agent
suitable for the treatment of pain to a patient receiving therapeutic
administration of compounds of formula (I) or (II). In a further aspect,
the invention provides the use of at least one agent suitable for the
treatment of pain in the manufacture of a medicament for adjunctive
therapeutic administration for the treatment of pain in a patient
receiving therapeutic administration of compounds of formula (I) or (II).
The invention further provides at least one agent suitable for the
treatment of pain for adjunctive therapeutic administration for the
treatment of pain in a patient receiving therapeutic administration of
compounds of formula (I) or (II).

[0414] In a further aspect, the invention provides a method of treatment
of pain by simultaneous therapeutic administration of compounds of
formula (I) or (II) in combination with at least one agent suitable for
the treatment of pain. The invention further provides the use of a
combination of compounds of formula (I) or (II) and at least one agent
suitable for the treatment of pain in the manufacture of a medicament for
simultaneous therapeutic administration in the treatment of pain. The
invention further provides a combination of compounds of formula (I) or
(II) and at least one agent suitable for the treatment of pain for
simultaneous therapeutic administration in the treatment of pain. The
invention further provides the use of compounds of formula (I) or (II) in
the manufacture of a medicament for simultaneous therapeutic
administration with at least one agent suitable for the treatment of pain
in the treatment of pain. The invention further provides compounds of
formula (I) or (II) for use for simultaneous therapeutic administration
with at least one agent suitable for the treatment of pain in the
treatment of pain. The invention further provides the use of at least one
agent suitable for the treatment of pain in the manufacture of a
medicament for simultaneous therapeutic administration with compounds of
formula (I) or (II) in the treatment of pain. The invention further
provides at least one agent suitable for the treatment of pain for
simultaneous therapeutic administration with compounds of formula (I) or
(II) in the treatment of pain.

[0415] Examples of agents suitable for the treatment of pain that are
useful in the present invention include, but are not limited to: NSAIDs
(Nonsteroidal Antiinflammatory Drugs), anti-convulsant drugs such as
carbamazepine and gabapentin, sodium channel blockers, anti-depressant
drugs, cannabinoids and local anaesthetics.

[0417] It will be appreciated by those skilled in the art that the
compounds according to the invention may advantageously be used in
conjunction with one or more other therapeutic agents, for instance,
antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1
antagonists, selective serotonin reuptake inhibitors (SSRI),
noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants,
dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1 B
antagonists, 5HT1 D antagonists, D1 agonists, M1 agonists and/or
anticonvulsant agents, as well as cognitive enhancers.

[0418] Suitable 5HT3 antagonists which may be used in combination of the
compounds of the inventions include for example ondansetron, granisetron,
metoclopramide.

[0419] Suitable serotonin agonists which may be used in combination with
the compounds of the invention include sumatriptan, rauwolscine,
yohimbine, metoclopramide.

[0420] Suitable SSRIs which may be used in combination with the compounds
of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine,
paroxetine, indalpine, sertraline, zimeldine.

[0421] Suitable SNRIs which may be used in combination with the compounds
of the invention include venlafaxine and reboxetine.

[0422] Suitable tricyclic antidepressants which may be used in combination
with a compound of the invention include imipramine, amitriptiline,
chlomipramine and nortriptiline.

[0423] Suitable dopaminergic antidepressants which may be used in
combination with a compound of the invention include bupropion and
amineptine.

[0424] Suitable anticonvulsant agents which may be used in combination of
the compounds of the invention include for example divalproex,
carbamazepine and diazepam.

[0425] The following examples serve to explain the invention without
limiting it.

[0426] The compounds were characterized by mass spectrometry, generally
recorded via HPLC-MS in a fast gradient on C18-material
(electrospray-ionisation (ESI) mode).

[0428] To a solution of 0.245 mmol of
2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid
in 2 ml dry THF were added at room temperature 0.736 mmol borane dimethyl
sulphide complex and the mixture was stirred over night. The mixture was
diluted with EtOAc and washed with saturated Na2CO3 solution
and brine. The aqueous layer was extracted with EtOAc. The combined
organic layers were washed, dried over MgSO4 and filtered.
Evaporation of the solvent gave 60 mg of a pale yellow oil (93%).

[0431] To a solution of 0.380 mmol of
tert-butyl-7-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate in
2.5 ml CH2Cl2 were added at 0° C. 1.139 mmol Et3N
and 0.456 mmol tribromophosphine. The mixture was allowed to warm to room
temperature and stirred for 1 h. To the reaction mixture were added
saturated NaHCO3 solution and EtOAc. The aqueous layer was extracted
with EtOAc. The combined organic layers were washed, dried over
MgSO4 and filtered. Evaporation of the solvent gave 105 mg of crude
material that was purified by flash chromatography to yield 76 mg of
colorless oil (61.3%).

[0434] To a solution of 21.76 mmol of
tert-butyl-7-(bromomethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate in
80 ml DMF were added at 0° C. 65.3 mmol sodium cyanide in small
portions. The mixture was stirred at room temperature for 2 h. Brine
solution was added to the mixture and the aqueous phase was extracted
with EtOAc. The combined organic layers were washed with brine, dried
over MgSO4 and filtered. Evaporation of the solvent gave 5.6 g of a brown
oil. The material was purified by flash chromatography to yield 1.63 g of
a pale yellow solid (27.5%).

[0437] To a solution of 0.231 mmol
tert-butyl-7-(cyanomethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate in 2
ml ethanol were added 0.278 mmol of NaOEt solution (21%) and 0.254 mmol
benzaldehyde. The mixture was stirred at room temperature over night. The
mixture was diluted with ethanol and H2O, and a white precipitation
observed. The solid was filtered off and washed with ethanol and
H2O. The white solid was dissolved in methanol. Evaporation of the
solvent gave 64 mg (77%) of solid material.

[0440] To a suspension of 0.178 mmol of
(Z)-tert-butyl-7-(1-cyano-2-phenylvinyl)-3,4-dihydroisoquinoline-2(1H)-ca-
rboxylate in 2 ml ethanol were added at 0° C. 0.178 mmol of sodium
borohydride. The mixture was allowed to warm to room temperature and
stirred for 3 d. The mixture was poured on ice water and citric acid (5%)
was added until acidic. The aqueous phase was extracted with EtOAc. The
combined organic phase was washed with brine, dried over MgSO4, and
filtered. Evaporation of the solvent gave 61.2 mg (95%) of a crude
slightly yellow oil, that was directly submitted to Boc deprotection.

1.6 3-Phenyl-2-(1,2,3,4-tetrahydroisoquinolin-7-yl)propanenitrile

##STR00037##

[0442] 0.171 mmol
tert-butyl-7-(1-cyano-2-phenylethyl)-3,4-dihydroisoquinoline-2(1H)-carbox-
ylate were dissolved in 1.3 ml formic acid and stirred at room temperature
for 1 h. After addition of saturated NaHCO3 solution the mixture was
extracted with EtOAc. The combined organic layers were dried over
MgSO4 and filtered. Evaporation of the solvent gave 38.5 mg of solid
material (86%).

[0445] To a solution of 0.135 mmol
3-phenyl-2-(1,2,3,4-tetrahydroisoquinolin-7-yl)propanenitrile in 2 ml
CH2Cl2 were added 0.203 mmol DMAP and 0.162 mmol
1-methyl-1H-imidazole-4-sulfonyl chloride. The mixture was stirred at
room temperature for 3 h. Additional 0.162 mmol
1-methyl-1H-imidazole-4-sulfonyl chloride were added and the mixture was
stirred for 3 d. The mixture was diluted with CH2Cl2 and washed
with 1N HCl, saturated NaHCO3 and H2O. The combined aqueous
layers were extracted with CH2Cl2. The combined organic phase
was dried over MgSO4 and filtered. Evaporation of the solvent gave
90 mg of the crude material. The material was purified by flash
chromatography to yield 53 mg of a white solid (97%).

[0448] The synthesis was performed starting from 0.123 mmol of
2-(2-(1-methyl-1H-imidazol-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7--
yl)-3-phenylpropanenitrile, which was dissolved in THF (1 ml), after which
0.37 mmol of BH3 THF complex (1 M in THF) was added at 0° C.
The mixture was warmed to room temperature and stirred for 2 h. The
mixture was diluted with CH2Cl2 and washed with 1 N HCl,
saturated NaHCO3 and H2O. The aqueous phase was extracted with
CH2Cl2. Combined organic phase was dried over MgSO4 and
filtered. Evaporation of the solvent gave 50 mg of the crude material.
The material was purified by flash chromatography to yield 11 mg of a
white solid (22%).

[0451] 2-(2-(1-methyl-1H-pyrazol-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinol-
in-7-yl)-3-phenylpropan-1-amine was prepared in analogy to example 1 using
1-methyl-1H-pyrazole-4-sulfonyl chloride in place of
1-methyl-1H-imidazole-4-sulfonyl chloride.

[0455] 2-(2-(Cyclopropylmethylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl-
)-3-phenylpropanenitrile was prepared in analogy to example 1 using
cyclopropylmethanesulfonyl chloride in place of
1-methyl-1H-imidazole-4-sulfonyl chloride.

[0457] 2-(2-(Cyclopropylmethylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl-
)-3-phenylpropanenitrile was dissolved in methanol and hydrogenated using
H-Cube technology (Raney-Ni cartridge, 1 bar, full H2 mode). The
reaction mixture was concentrated and 1 N HCl was added. Then H2O
and CH2Cl2 were added and the aqueous phase was extracted by
CH2Cl2. The aqueous phase was freeze dried and gave 2.8 mg
(8.7%) of a hygroscopic solid.

[0460] 0.058 mmol of
2-(2-(1-methyl-1H-imidazol-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7--
yl)-3-phenylpropan-1-amine (example 1) were dissolved in 2 ml of methanol.
A solution of formaldehyde (0.351 mmol, 37%) and 0.351 mmol of sodium
cyanotrihydroborate were added and the mixture was stirred at room
temperature over night. H2O was added to the reaction mixture and
the aqueous phase was extracted with CH2Cl2. The combined
organic phases were dried over MgSO4 and filtered. The filtrate was
concentrated to 6 mg of crude solid material. The solid was washed with
diisopropyl ether and dissolved in methanol. An equimolar amount of 1 N
HCl was added and the volatiles removed in vacuo. The residue was washed
with diethyl ether, dissolved in H2O, acidified with 1 N HCl and
washed with additional diethyl ether. The aqueous phase was freeze dried
to give 4.6 mg of the desired product (16.5%).

[0463] 0.022 mmol of
2-(2-(1-methyl-1H-pyrazol-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-y-
l)-3-phenylpropan-1-amine (example 2) were dissolved in 1 ml acetonitrile.
To this solution 0.022 mmol of iodomethane and 0.044 mmol of cesium
carbonate were added at room temperature and the mixture was stirred over
night. H2O and CH2Cl2 were added to the reaction mixture
and the aqueous phase was extracted with CH2Cl2. The combined
organic phases were dried over MgSO4 and filtered. The filtrate was
concentrated to yield 4 mg of crude solid material. The solid was washed
with diethyl ether and dried in vacuo. 0.5 mg of the desired product were
obtained (4.6%).

[0464] ESI-MS [M+H.sup.+]=453 Calculated for
C25H33N4O2S=453

Biological Testing

[0465] 1. [3H]-Glycine uptake into recombinant CHO cells expressing
human GlyT1: Human GlyT1c expressing recombinant hGlyT1c--5_CHO
cells were plated at 20,000 cells per well in 96 well Cytostar-T
scintillation microplates (Amersham Biosciences) and cultured to
sub-confluency for 24 h. For glycine uptake assays the culture medium was
aspirated and the cells were washed once with 100 μl HBSS (Gibco BRL,
#14025-050) with 5 mM L-Alanine (Merck #1007). 80 μl HBSS buffer were
added, followed by 10 μl inhibitor or vehicle (10% DMSO) and 10 μl
[3H]-glycine (TRK71, Amersham Biosciences) to a final concentration
of 200 nM for initiation of glycine uptake. The plates were placed in a
Wallac Microbeta (PerkinElmer) and continuously counted by solid phase
scintillation spectrometry during up to 3 hours. Nonspecific uptake was
determined in the presence of 10 μM Org24598. IC50 calculations
were made by four-parametric logistic nonlinear regression analysis
(GraphPad Prism) using determinations within the range of linear increase
of [3H]-glycine incorporation between 60 and 120 min.